Epigenomic therapies: the potential of targeting SIRT6 for the treatment of pancreatic cancer

Demir, Ihsan Ekin; Ceyhan, Güralp O.; Friess, Helmut

doi:10.1080/14728222.2017.1265507

Cited by 9 publications

(9 citation statements)

References 9 publications

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“…Overexpression of SIRT6 promoted autophagy and reduced apoptosis in HK-2 cells.It was found that DNA-PKcs and CtIP deacetylation may be used as crucial for SIRT6mediated DNA repair, which provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia [40]. There are also studies suggesting that the modulation of SIRT6 activity may be a potential new therapeutic method for diabetic atherosclerotic and pancreatic cancer [41,42].…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

et al. 2019

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Sirtuin 6 (SIRT6) has the function of regulating autophagy. The aim of this study was to investigate the mechanism through which SIRT6 relieved acute kidney injury (AKI) caused by sepsis. The AKI model was established with lipopolysaccharides (LPS) using mice. Hematoxylin-eosin (HE) staining and streptavidin-perosidase (SP) staining was used to observe kidney tissue and test SIRT6 and LC3B proteins in kidney. Enzyme-linked immunosorbent assay (ELISA) was performed to detected the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations. Cell counting kit-8 (CCK-8) assay and flow cytometry were carried out to test the cell viability and apoptosis rate respectively. Protein and mRNA were determined by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). AKI induced by LPS had self-repairing ability. At 12 h after modeling, the expression levels of TNF-α, IL-6, SIRT6 and LC3B-II/LC3B-I were first significantly increased and were then significantly decreased at 48 h after modeling. LPS inhibited the growth of HK-2 cells and promoted the expressions of TNF-α, IL-6, SIRT6 and LC3B. Overexpression of SIRT6 down-regulated the secretion of TNF-α and IL-6 induced by LPS. SIRT6 overexpression inhibited apoptosis induced by LPS and promoted autophagy in HK-2 cells. Silencing of the SIRT6 gene not only promoted the secretion of TNF-α and IL-6 by HK-2 cells, but also promoted apoptosis and reduced autophagy. LPS up-regulated the expression of SIRT6 gene in HK-2 cells. Overexpression of the SIRT6 gene could inhibit apoptosis and induce autophagy, which might be involved in repairing kidney damage caused by LPS.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

et al. 2019

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“…On the basis of previous studies showing that miR-221 may act as an oncogenic factor in certain malignancies (reviewed in [ 11 ]), we began the present investigation assessing that the levels of the endogenous miR-221 are higher in crucial players of the tumor microenvironment as CAFs and in both MDA-MB 231 and SkBr3 breast cancer cells respect to normal fibroblasts and non-transformed MCF10A breast cells (Fig. 1a ).…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, miR-144 was shown to induce stimulatory effects in breast cancer cells [ 9 ] and miR-103/miR-107 were associated with a poor outcome in patients affected by triple-negative breast cancer [ 10 ]. Next, the involvement of miR-221/miR-222 has been recently shown in many tumors [ 11 ]. For instance, miR-222 was implicated in the progression [ 12 ] and the drug-resistance [ 13 ] of breast cancer, whereas miR-221 elicited stimulatory effects in diverse types of malignancies down-regulating certain onco-suppressor genes [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling

Santolla

Lappano

Cirillo

et al. 2018

J Exp Clin Cancer Res

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BackgroundMicroRNA (miRNAs) are non-coding small RNA molecules that regulate gene expression by inhibiting the translation of target mRNAs. Among several dysregulated miRNAs in human cancer, the up-regulation of miR-221 has been associated with development of a variety of hematologic and solid malignancies. In this study, we investigated the involvement of miR-221 in breast cancer.MethodsTaqMan microRNA assay was used to detect the miR-221 levels in normal cells and in MDA-MB 231 and SkBr3 breast cancer cells as well as in main players of the tumor microenvironment, namely cancer-associated fibroblasts (CAFs). miR-221 mimic sequence and locked nucleic acid (LNA)-i-miR-221 construct were used to induce or inhibit, respectively, the miR-221 expression in cells used. Quantitative PCR and western blotting analysis were performed to evaluate the levels of the miR-221 target gene A20 (TNFAIP3), as well as the member of the NF-kB complex namely c-Rel and the connective tissue growth factor (CTGF). Chromatin immunoprecipitation (ChIP) assay was performed to ascertain the recruitment of c-Rel to the CTFG promoter. Finally, the cell growth and migration in the presence of LNA-i-miR-221 or silencing c-Rel and CTGF by specific short hairpin were assessed by cell count, colony formation and boyden chambers assays. Statistical analysis was performed by ANOVA.ResultsWe first demonstrated that LNA-i-miR-221 inhibits both endogenous and ectopic expression of miR-221 in our experimental models. Next, we found that the A20 down-regulation, as well as the up-regulation of c-Rel induced by miR-221 were no longer evident using LNA-i-miR-221. Moreover, we established that the miR-221 dependent recruitment of c-Rel to the NF-kB binding site located within the CTGF promoter region is prevented by using LNA-i-miR-221. Furthermore, we determined that the up-regulation of CTGF mRNA and protein levels by miR-221 is no longer evident using LNA-i-miR221 and silencing c-Rel. Finally, we assessed that cell growth and migration induced by miR-221 in MDA-MB 231 and SkBr3 breast cancer cells as well as in CAFs are abolished by LNAi-miR-221 and silencing c-Rel or CTGF.ConclusionsOverall, these data provide novel insights into the stimulatory action of miR-221 in breast cancer cells and CAFs, suggesting that its inhibition may be considered toward targeted therapeutic approaches in breast cancer patients.

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“…Recent studies show a series of significant alterations of the acetylation process in PDAC, as well as mutations in the histone acetylase EP300 [33]. Furthermore, the SIRT6 gene is associated with the deacetylation of histone H3 at lysine residues 9 and 56, thus increasing the expression of the SIRT6 gene associated with PDAC metastasis by deacetylation of p53 and FOXOA3 [62](see Figure 3b). For instance, the activation of KRAS and increased expression of the c-Myc transcription factor promote PDAC metastasis [13].…”

Section: Schematic Diagram On the Role Of Hdacs In Pdac (A) Hdacs Mementioning

confidence: 95%

Epigenetics: Dissecting Gene Expression Alteration in PDAC

Abukiwan¹,

Berger²

2019

DNA Repair- An Update

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Pancreatic cancer is the fourth leading cause of cancer deaths, with a low 5-year survival rate of about 7% due to its highly invasive nature. Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of all pancreatic cancer cases. At the time of detection, around 80% of cases harbor metastases due to the lack of early diagnosis. For decades, scientists have primarily focused on dissecting the origin of pancreatic cancer through genetic alterations and their contribution to diagnosis. Recently, PDAC research has turned into epigenetics to revolutionize our understanding about the silencing of critical regulatory genes. Epigenetic events can be divided mechanistically into various components, including DNA methylation, histone posttranslational modification, nucleosome remodeling, and regulation of transcription or translation by microRNA. The identified epigenetic processes in PDAC contribute to its specific epigenotype and are correlated phenotypic features. Strikingly, some of them have been suggested to have potential as cancer biomarkers, for disease monitoring, prognosis, and risk validation. As epigenetic aberrations are reversible, their correction will become as a promising therapeutic target.

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Epigenomic therapies: the potential of targeting SIRT6 for the treatment of pancreatic cancer

Cited by 9 publications

References 9 publications

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling

Epigenetics: Dissecting Gene Expression Alteration in PDAC

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